Oct 7, 2019: The Nobel Assembly at Karolinska Institutet has decided to award the 2019 Nobel Prize in Physiology or Medicine jointly to William G. Kaelin Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza, for their discoveries of How Cells Sense and Adapt to Oxygen Availability.
Why is the discovery so important? What has been discovered anyway? This article gives you a quick look at the research contents with simple, easy-to-understand words.
Significance of the discovery
Comparing to the research itself, I think “how the research benefits us” concerns more people.
Oxygen sensing is central to a large number of diseases (See the picture from nobelprize.org).
By understanding how cells sense and adapt to low oxygen conditions, scientists can learn more about, for example, how cancer cells proliferate so effectively in a low-oxygen environment like within tumors, so that new treatment or medicine for cancer may be developed.
In fact, academic laboratories and pharmaceutical companies have begun to develop drugs that can interfere with different diseases states by either activating or blocking the oxygen-sensing machinery.
How cells sense and adapt to oxygen availability
Oxygen (O2) is essential to all cells’ activities. But there are some conditions, high altitudes for example, under which our bodies cannot get enough oxygen supply, and the cells need to adapt to low oxygen levels (hypoxia).
EPO and EPO gene
There is a key physiological response to hypoxia, which is the rise in levels of the hormone erythropoietin (EPO). EPO can increase the production of red blood cells (erythropoiesis), and is controlled by EPO gene.
However, how the adaption process was controlled by oxygen was unclear. When looking into the process, scientists found that the oxygen sensing mechanism was present in all tissues, not only in the kidney cells, as people previously thought. This was an important discovery because it showed that the oxygen sensing mechanism was general and functional in many different cell types.
HIF: HIF-1α and ARNT
Semenza discovered a protein complex that binds to the EPO DNA segment in an oxygen-dependent manner. The complex is named the hypoxia-inducible factor (HIF). HIF consists of two different DNA-binding proteins, HIF-1α and ARNT.
The puzzle has been solved a little. Now the question is: how does oxygen influence HIF, to make it control the EPO gene?
HIF-1α and its degradation
When oxygen levels are high, cells contain very little HIF-1α; while when oxygen levels are low, the amount of HIF-1α increases, so that it can bind to and thus regulate the EPO gene and other related HIF-binding DNA segments.
Scientists found that a cellular machine called the proteasome degrades HIF-1α when the oxygen levels are normal. A small peptide, ubiquitin, is added to the HIF-1α protein as a tag for proteins waiting for degradation in the proteasome.
When the oxygen levels are low, HIF-1α is protected from being degraded.
So next question is: how does ubiquitin bind to HIF-1α in an oxygen-dependent manner?
VHL protein
Willian Kaelin Jr. found that the gene of an inherited syndrome, von Hippel-Lindau’s disease (VHL disease), encodes a protein that prevents the onset of cancer.
Cancer cells lacking a functional VHL gene express abnormally high levels of hypoxia-regulated genes; but when the VHL gene was introduced into cancer cells, the levels were restored. This showed that VHL was somehow involved in controlling responses to hypoxia.
Other clues showed that VHL is part of a complex that labels proteins with ubiquitin, marking them for degradation in the proteasome. The conclusion was: VHL can physically interact with HIF-1α and is required for its degradation at normal oxygen levels. In another word, VHL is linked with HIF-1α.
Last question: how do oxygen levels regulate the interaction between VHL and HIF-1α?
Prolyl hydroxylation
Research shows that a protein modification, prolyl hydroxylation, allows VHL to recognize and bind to HIF-1α. When the oxygen levels are normal, prolyl hydroxylation helps degrade HIF-1α; when the oxygen levels are low, it cannot promote HIF-1α degradation, allowing HIF-1α to bind to ARNT, so that hormone EPO is produced.
Conclusion
Let's look through the whole logic, or the orders of discoveries again.
1. How do cells survive in low oxygen levels: the EPO gene produces the EPO hormone, increasing the number of red blood cells.
2. Why does EPO gene start producing the EPO hormone: a complex called HIF binds to the EPO DNA segment to make it happen.
3. When does HIF appear: in low oxygen levels, HIF-1α enters the cell nucleus and combines with ARNT, producing HIF.
4. Why does HIF-1α only work in low oxygen levels: in normal oxygen levels, ubiquitin will mark HIF-1α, degrading it.
5. How does ubiquitin mark HIF-1α: VHL protein helps.
6. Why does VHL protein help: in normal oxygen levels, the prolyl hydroxylation allows VHL to help.
Therefore, when oxygen levels are low (hypoxia), VHL cannot help ubiquitin mark HIF-1α, so that HIF-1α is protected from degradation. It then associates with ARNT and binds to hypoxia-regulated genes.
When oxygen levels are normal, oxygen converts to hydroxyl groups and bind to HIF-1α, helping the VHL protein recognize and form a complex with HIF-1α, leading to its degradation.
See the picture from nobelprize.org.
The awarded mechanism for oxygen sensing has fundamental importance in physiology, for example for our metabolism, immune response and ability to adapt to exercise. Many pathological processes are also affected. Intensive efforts are ongoing to develop new drugs that can either inhibit or activate the oxygen-regulated machinery for treatment of anemia, cancer and other diseases.
